Psoriatic arthritis (PsA) is a form of inflammatory

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1 243 Psoriatic Arthritis Treatment Update Philip J. Mease, M.D. Psoriatic arthritis (PsA) is a form of inflammatory arthritis that occurs in approximately 10% to 30% of individuals with psoriasis, depending on the population studied. 1 Treatment choice should take into account effectiveness in several heterogeneous clinical domains: joints (synovitis), entheses (enthesitis), dactylitis, spine (spondylitis), and skin (psoriasis). Because the severity of the disease may vary between these domains, it is important to be comprehensive in evaluation, which includes close teaming with dermatology. Since it has been demonstrated that early and aggressive control of disease activity in the management of rheumatoid arthritis (RA) results in significantly better clinical and radiographic outcomes, 2,3 a similar paradigm of treating to target of remission or low disease activity state (LDAS) is now being studied in PsA in the TICOPA trial. It is anticipated that similar benefits will result from early and tight control intervention in the patient with risk factors for a moderate to severe disease course in PsA. To achieve tight control, one ideally assesses disease severity by way of history, physical exam, laboratory, and imaging assessments. Measures of joint and skin disease severity for clinical trials have been adopted from RA and psoriasis assessment tools. 4,5 Additional clinical domains important in PsA include enthesitis, dactylitis, and spine disease. These domains are now being measured in clinical trials so that we have the ability to assess the effectiveness of current and emerging therapies in domains beyond joints and skin (Table 1). 4,5 The Group for Research and Philip J. Mease, M.D., is at Seattle Rheumatology Associates, is the Director of the Division of Rheumatology Research, Swedish Medical Center, and is a Clinical Professor at the University of Washington School of Medicine, Seattle, Washington. Correspondence: Philip J. Mease, M.D., Seattle Rheumatology Associates, 1101 Madison Street,. Suite 1000, Seattle, Washington 98104; pmease@nwlink.com. Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and other groups are actively working to standardize these measures and ascertain if a composite disease activity score addressing all clinical domains of PsA can be developed that can be easily performed and meaningfully capture the impact of each domain on outcomes. 6 Coates led an exercise among GRAPPA members, based on review of hypothetical cases, which led to the definition of minimal disease activity (MDA) criteria for PsA (Table 2 ). 7 These criteria were validated by assessing patients in Gladman s patient cohort in Toronto 8 and in interventional trial datasets. 9 The development of this instrument is a step toward treatment to target in PsA. Pharmacotherapy A comprehensive review of the evidence for effectiveness of various PsA pharmacotherapy approaches has been conducted by GRAPPA in the process of developing international treatment recommendations (Table 3). 3,10-18 Patients with mild forms of musculoskeletal inflammation may use non-steroidal antiinflammatory drugs (NSAIDs), analgesics, low dose corticosteroids, or receive intra-articular or enthesial injections of steroids. 19,20 There is little trial evidence for the efficacy of these agents in PsA, since this evidence has been primarily developed in RA, ankylosing spondylitis (AS), and osteoarthritis (OA). 19,20 Oral Disease Modifying Anti-Rheumatic Drugs (DMARDs). Methotrexate (MT) is one of the most commonly used systemic medications in PsA, despite scant controlled trial data documenting efficacy The most recent trial, Methotrexate in Psoriatic Arthritis (MIPA), failed to demonstrate a statistically significant superiority of MT over placebo in the study s primary endpoint, the Psoriatic Arthritis Response Criteria (PsARC), or ACR 20, DAS28, Mease P. Psoriatic arthritis: treatment update. Bull NYU Hosp Jt Dis. 2011;69(3):243-9.

2 244 Bulletin of the NYU Hospital for Joint Diseases 2011;69(3):243-9 Table 1 Measures for Assessment of Psoriatic Arthritis in Clinical Trials 4,5 Domains Instruments Joint assessment 68/66 T/S joint count, ACR, DAS, PsARC Axial assessment BASDAI, BASFI, BASMI Skin assessment PASI, Target lesion, Global Pain VAS Patient global VAS (global, skin + joints) Physician global VAS (global, skin + joints) Function/QOL HAQ, SF-36, PsAQoL, DLQI Fatigue FACIT, Krupp, MFI, VAS Enthesitis assessment Mander, MASES, Leeds, Berlin, SPARCC, 4-point Dactylitis assessment Leeds, present/absent, acute/chronic Acute phase reactant ESR, CRP Imaging ray (modified Sharp or van der Heijde-Sharp), MRI, US Table 2 Minimal Disease Activity (MDA) Criteria in PsA 6 A patient is classified as in MDA when they meet 5 of 7 of the following criteria: Tender joint count 1 Swollen joint count 1 PASI 1 or BSA 3 Patient pain VAS 15 Patient global activity VAS 20 HAQ 0.5 Tender entheseal points 1 swollen or tender joint count, or acute phase reactants at 3 or 6 months but did show superiority at 6 months in patient and physician global measures. 21 These results do raise questions about whether patients should be expected to try MT before use of biologic therapy, but there were enough issues with the trial, such as a large number of dropouts, that we still fall back on clinical experience that some patients do appear to respond to MT. Whereas MT may benefit symptoms of arthritis and psoriasis in some patients, its ability to effectively treat enthesitis, dactylitis, and to inhibit structural damage has not been prospectively assessed. A 2-year retrospective analysis of matched PsA patients who were either on or off MT therapy did not show any difference in radiologic progression scores in the two groups. 22 Using evidence from AS, since not assessed in PsA, MT is not considered to be effective in treating spine disease. 13 The potential for MT-induced hepatotoxicity has been a special concern for dermatologists, based on the finding of greater hepatotoxicity in psoriasis than RA in older serial liver biopsy studies. 23 A current hypothesis is that this is at least partly related to the tendency of psoriasis patients and, to a lesser extent, PsA patients to be obese and have non-alcoholic hepatic steatosis ( fatty liver ) as a concomitant liver problem, as well as other factors, such as excessive alcohol use. Dermatologists, but not rheumatologists, have historically recommended periodic liver biopsy for safety monitoring. New guidelines for MT monitoring in dermatology do not require biopsy. 24 Although the combination of MT and tumor necrosis factor (TNF) inhibitors has in RA been shown to be superior in all clinical parameters of efficacy, including inhibition of structural damage, this has not been systematically assessed in PsA. A recent trial conducted in PsA patients, naïve to MT that compared infliximab plus MT versus MT monotherapy, demonstrated greater efficacy in clinical measures in the combination group. 25 In clinical practice, MT may sometimes be discontinued after initiation of biologic therapy if there is concern about hepatotoxicity and only be re-initiated if the patient experiences inadequate control of disease with biologic monotherapy. Although the largest number of controlled trials of traditional DMARD therapy in PsA have been conducted Table 3 PsA Treatments 9-17 Peripheral arthritis Skin and nail disease Axial disease Dactylitis Enthesitis NSAIDs Intra-articular steroids Topicals Physiotherapy Psoralen UVA/UVB DMARDS (MT, CsA, SSA, Lef) Biologics (anti-tnf antagonists) Anti-TNF = tumor necrosis factor inhibitor; CsA = cyclosporin A; DMARD = disease-modifying antirheumatic drugs; LEF = leflunomide; MT = methotrexate; NSAID = nonsteroidal anti-inflammatory drugs; SSZ = sulfasalazine.

3 245 with sulfasalazine, 19,20 its utility remains limited because of lack of effect in the skin and occasional gastrointestinal intolerability. Leflunomide, a pyrimidine antagonist, has shown effectiveness in PsA and is formally approved for PsA treatment in Europe at a dose of 20 mg per day. 19,20 Cyclosporine can achieve rapid improvement of the skin lesions of psoriasis, but evidence for its effectiveness in musculoskeletal disease is scant, and its utility is limited by concerns regarding the adverse effects of hypertension and renal insufficiency. 19,20 It has been used in combination with adalimumab. 26 Biologic Response Modifiers Biologic agents currently approved for treatment of PsA are the anti-tnf compounds etanercept, infliximab, adalimumab, and golimumab, and a fifth agent, certolizumab, is being studied. TNFα inhibitors have established efficacy in all clinical domains of PsA, including joints, skin, enthesitis, and dactylitis, significantly improve function and quality of life, and inhibit structural damage. Efficacy in the spine is inferred from efficacy in AS. The efficacy and safety of etanercept in PsA was pivotally established in a phase 3 trial in 205 patients. 27 Approximately half of the patients were on background MT and stratified, based on MT use, to etanercept (50 mg per week) or placebo. Significant improvement was demonstrated in joints, inhibition of structural damage (demonstrated radiographically), skin, function, and quality of life (QOL). Two-year extension data demonstrated sustained efficacy in all domains. 28 Background MT made no difference on outcomes. The drug was well tolerated and no safety issues emerged apart from those seen in clinical trial and general clinical experience with etanercept in RA. More recently, the Psoriasis Randomized Etanercept STudy in Subjects with Psoriatic Arthritis (PRESTA) trial assessed 752 patients with highly active PsA and psoriasis (average body surface area [BSA] involvement with psoriasis 31%) randomized to a standard dose of etanercept approved for PsA, 50 mg per week (Group 1) versus a dose approved for psoriasis of 50 mg twice a week for 12 weeks followed by 50 mg per week thereafter (Group 2). 29 ACR and enthesitis scores improved similarly in both dose arms at 12 and 24 weeks. Of those patients with enthesitis assessed by Achilles tendon and plantar fascia insertion tenderness, 65% in Group 1 and 66% in Group 2 had no enthesitis at week 12, and 76% (Group 1) and 75% (Group 2) had none at week 24. Similarly improved dactylitis scores were noted, demonstrating the ability of etanercept to effectively treat these aspects of PsA, but no additional advantage was achieved in musculoskeletal domains by using the higher dose initially. On the other hand, substantial improvement of skin lesions occurred to a greater extent in the higher dose group, with PASI 75 response at week 12 seen in 55% versus 36% (p < 0.001) in Group 2 and 1, respectively, and 70% and 62% at week 24 (p < 0.05). The effectiveness of infliximab, a chimeric monoclonal antibody administered 5 mg/kg intravenously, was demonstrated in PsA in a pivotal trial of 200 patients. 30 As with etanercept, efficacy in all clinical domains of PsA, including inhibition of joint damage, was established. In a study performed in Russia, 115 patients with relatively early PsA (mean disease duration 2.8 to 3.7 years) were randomized in an open fashion to receive methotrexate monotherapy (15 mg/wk) or a combination of methotrexate (15 mg/wk) and infliximab, 5 mg/kg, in the standard infusion regimen employed for this agent. 25 At 16 weeks, patients in the combination arm had superior outcomes, with ACR 20/50/70, DAS28 remission, and PASI 75/90 responses in 86%/73/49, 69%, and 97%/71, respectively, while in the MT monotherapy arm, these results were 67/40/19, 29, and 54/29%, respectively. These results suggest that earlier intervention in PsA can result in very substantial improvements of disease activity, especially as seen in the combination of anti-tnf and MT therapy but also provides a demonstration of the potential effectiveness of MT monotherapy in such an early cohort. Adalimumab, a fully human anti-tnf-a monoclonal antibody administered subcutaneously in a dosage of 40 mg every other week, was studied in the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) (n = 313). 31 As with other anti-tnfs, significant benefit in joints, skin, function, QOL, inhibition of radiographic damage, and fatigue was demonstrated. A 2-year extension study demonstrated sustained ACR and PASI responses and persistent inhibition of x-ray progression. 32 Golimumab is a fully human anti-tnf-α monoclonal antibody that is approved in a 50 mg monthly subcutaneous application for PsA, based on a study of 405 patients. 33 At this dose, at the primary endpoint of 14 weeks, ACR 20 was achieved by 51% versus 9% in the placebo group (p < 0.001), and ACR 50/70 was achieved by 30% and 12%, respectively. PASI 75 response was achieved by 40% at week 14 in 109 patients and 56% at week 24 in 102 patients with at least 3% BSA involvement evaluable for PASI. Of those patients with enthesitis assessed by the Maastricht enthesitis index (MASES), significantly more patients showed resolution of enthesitis compared to placebo. Nail changes also significantly improved as did measures of physical function. These improvements were sustained at 104 weeks in an open extension phase of this trial. 34 Inhibition of progressive joint damage at one year has been reported. 35 Safety experience was commensurate with that of other anti-tnf agents in PsA. A newer anti-tnfα agent, certolizumab pegol, approved for treatment of RA is a subcutaneously administered pegylated Fab fragment, which is being studied in PsA. Although there is scant trial evidence, 36 experience in management of PsA with currently available anti-tnf

4 246 Bulletin of the NYU Hospital for Joint Diseases 2011;69(3):243-9 agents suggests that when a clinician switches from one of these agents to another, if the first has lost efficacy or caused side effects, a substantial percentage of patients will respond to another medication in this class. Inflammatory spine disease has not been formally assessed in PsA clinical trials due to a number of factors including the variability of expression of this clinical domain in PsA. Anti-TNF medications have shown significant efficacy for axial manifestations of AS. 37 Although NSAIDs have been shown to be beneficial for axial symptoms of AS, methotrexate, sulfasalazine, and leflunomide have not, 37 suggesting that anti-tnfs are the preferred class of medicine to be used in those with inadequate response to NSAIDs. We do not have controlled evidence to know if the same holds true in PsA, although extrapolation of the AS experience to PsA seems reasonable and has been adopted in the GRAPPA treatment recommendations. 10 The anti-tnfα medications have shown the greatest efficacy of any treatment to date in the various clinical aspects of PsA. Their efficacy in treating joint disease activity, inhibiting structural damage, and improving function and quality of life are similar, and the effects on skin are similar, depending on the dose utilized. Safety concerns are present, such as risk for infection, but no new concerns have arisen in the PsA population compared to the more extensively studied RA patient population. PsA Pharmacotherapy: Agents Approved in Other Indications Which Have or are Being Tested in PsA Co-stimulatory Blockade Agents These agents modulate T-cell activation by inhibiting the second receptor signal involved. Alefacept is a fully human fusion protein that blocks interaction between LFA-3 on the antigen-presenting cell and CD2 on the T cell or by attracting natural killer lymphocytes to interact with CD2 to yield apoptosis of particular T-cell clones. It is approved for treatment of psoriasis in the USA and is administered weekly as a 15 mg intramuscular injection in an alternating 12 weeks on and 12 weeks off regimen in order to allow return of depleted CD4 cells in the off period. A phase 2 controlled trial of alefacept in PsA (n = 185) showed that 54% of patients given a combination of alefacept and MT had an ACR 20 response as compared to 23% in the MT alone group (p < 0.001) at week 24 and showed sustained responses in patients undergoing a second course. 38,39 PASI 75 results were 28% and 24%, respectively. Modesty of efficacy of this agent has limited its use in PsA, but it is a consideration in patients who have failed or had side effects with other medications. Abatacept (CTLA4-Ig) is a recombinant human fusion protein that binds to the CD80/86 receptor on an antigenpresenting cell, thus blocking the second signal activation of the CD28 receptor on the T cell. It is administered intravenously monthly and has been approved for use in RA based on its ability to improve composite joint scores, function, and inhibit radiographic progression. Recently, a subcutaneous form administered weekly has been approved for RA. A trial in psoriasis has been conducted and shown efficacy. 40 This drug has been evaluated in a phase 2 trial in PsA. In the standard dose arm of 10 mg/kg IV monthly (n = 40), 48% achieved ACR 20 response at day 169 compared to 19% in the placebo arm (p = 0.006), although there was greater efficacy in the sub-group not previously exposed to anti-tnf therapy. 41 Efficacy in skin lesions in this trial was modest, with PASI 75 response in the 10 mg/kg arm occurring in 14% versus 5% in the placebo group. This agent has been well-tolerated, with the main safety issue being the risk for infection, analogous to other biologic agents. IL-12/23 inhibition Both IL-12 and IL-23 are over-expressed in psoriasis plaques. IL-23 is a key cytokine, which stimulates the proliferation and activation of Th17 lymphocytes, recently appreciated as important in a variety of inflammatory diseases, including psoriasis, PsA, and AS. 42 Ustekinumab, an IL12/23 inhibitor administered subcutaneously, has shown significant efficacy in psoriasis for which it is approved. 43 This agent has also shown efficacy in a preliminary PsA study. 44 This was a placebo-controlled cross-over study in which patients were treated weekly for 4 weeks followed by placebo injections. At week 12, 42% of the initially treated group (n = 76) achieved an ACR20 response compared to 14% in the placebo group (p = ). The drug was generally well tolerated. A larger phase 3 study will be reporting soon. B Lympocyte Ablation/Modulation Rituximab, an anti-cd20 agent that ablates B lymphocytes and is approved in the treatment of lymphoma and RA (1,000 mg x 2 separated by 2 weeks, every 6 months), was assessed in an open label trial of 20 patients using the RA dosing regimen. It demonstrated modest efficacy for arthritis, primarily in a subgroup of patients not previously exposed to anti-tnf therapy but showed little effect for arthritis in those previously TNF inhibitor-exposed or in the skin. 45 The latter is perhaps not surprising, given the paucity of B cells in psoriasis skin lesions. One might consider off-label use of this agent in PsA patients with history of or current lymphoma, in whom TNF inhibitors may not want to be used. IL-6 Inhibitors IL-6 is a pleiotropic cytokine that can promote inflammation via its stimulatory effect on multiple pro-inflammatory cells, not unlike TNFα. A monoclonal antibody that inhibits the IL-6 receptor, tocilizumab, has shown significant effectiveness in RA, for which it is approved in intravenous form. A pilot study with this agent in PsA is being undertaken. Several other IL-6 inhibitors, which either inhibit the receptor

5 247 Table 4 Defining Disease Severity in PsA Clinical Domains 9 Peripheral arthritis Mild Moderate Severe < 5 joints No damage on x-ray No LOF QOL-minimal impact Pt. evaluation mild Skin Disease BSA < 5, PASI < 5, asymptomatic Spinal Disease Mild pain No loss of function Enthesitis 1-2 sites No loss of function Dactylitis Pain absent to mild Normal function 5 joints (S or T) Damage on x-ray IR to mild Rx Mod LOF Mod impact on QOL Pt. evaluation mod Non-response to topicals, DLQI, PASI < 10 Loss of function or BASDAI > 4 5 joints (S or T) Severe damage on x-ray IR to mild-mod Rx Severe LOF Severe impact on QOL Pt. evaluation severe BSA > 10, DLQI > 10 PASI > 10 Failure of response > 2 sites or loss of function Loss of function or > 2 sites and failure of response Erosive disease or functional loss Failure of response S = swollen; T = tender; LOF = loss of physical function; IR = inadequate response; BSA = body surface area; BASDAI = Bath Ankylosing Spondylitis Disability Activity; Index; PASI = Psoriasis Activity Severity Score; QOL = quality of life; DLQI = Dermatology Life Quality Index. or the cytokine directly, will be studied in PsA. The majority of these will be administered subcutaneously. Given the proclivity of PsA patients to have metabolic syndrome (obesity, hypertension, hyperlipidemia), and thus a proclivity to have fatty liver, it will be important to control hyperlipidemia and monitor for LFT abnormalities, both known adverse effects of IL-6 inhibitors. Emerging Agents (Agents Not Yet Approved for Any Indication) IL-17 Inhibitors IL-17, a pro-inflammatory cytokine produced by TH17 cells, is an attractive target in diseases in which the TH17 cell plays a prominent role, including RA, psoriasis, and the spondyloarthropathies. 42 Phase 2 trials in RA and psoriasis have been conducted with several emerging IL- 17 inhibitors. Efficacy has been outstanding in psoriasis and good in RA. For example, with the Novartis IL-17A inhibitor, secukinumab, PASI 75 response at 4 weeks was 58%, while the placebo response was 4% (p = ). 46 In RA, the ACR 20 response with secukinumab was 46% at 6 weeks, while the placebo response was 27% (p = 0.12). 46 Although the RA response was somewhat modest, data from a phase 2 trial in AS demonstrated significant benefit in that the treatment group showed an ASAS 40 response in 61% of subjects and 17% of placebo-treated subjects, 47 which raises the possibility that this agent may show greater benefit in the spondyloarthritides and psoriasis than in RA. With the Amgen IL-17 receptor antagonist, AMG827, PASI 75 response at 12 weeks was 77% with 140 mg dosing and 82% with 210 mg. 48 The preliminary safety profile of both agents appears favorable. Given that the biologic and clinical profile of PsA includes characteristics of both psoriasis and RA, it is anticipated that efficacy will be demonstrated in joints and skin of PsA patients. The degree of effectiveness in domains such as enthesitis, dactylitis, and spine disease remains to be determined. JAK Inhibtors There are several emerging oral small molecule agents, such as the JAK inhibitors, that will soon be tested in PsA. These agents inhibit intracellular signal transduction, inhibiting the receptor signal of a number of pro-inflammatory cytokines, thus modulating immune response. Of these, the one furthest along is tofacitinib, which has shown significant efficacy in RA and psoriasis. Treatment Recommendations The GRAPPA group has published a set of treatment recommendations for the various clinical domains of PsA. 10 This was based on formal literature reviews of therapies for disease of peripheral joints, spine, skin and nails, enthesitis, and dactylitis and discussions among GRAPPA members (rheumatologists and dermatologists) A disease severity grid was developed (Table 4) 10 that categorizes each domain as mild, moderate, or severe based on measures of disease severity and impact on function and QOL in order to help the clinician with treatment decisions. The paper proceeds to recommend specific treatments for each clinical domain according to level of severity and impact. 10 In parallel, a task force composed primarily of dermatologists has developed recommendations for treatment of PsA. 49 Disclosure Statement The author has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony. Acknowledgments The author would like to acknowledge the assistance of Cathy Loeffler in preparation of the manuscript. References 1. Chandran V, Raychaudhuri SP. Geoepidemiology and environmental factors of psoriasis and psoriatic arthritis. J

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